Prenylation inhibitors containing dimethylcyclobutane and methods of their synthesis and use

a technology of dimethylcyclobutane and inhibitors, which is applied in the field of compound compounds, can solve the problems of difficult synthesizing and purifying, lethal to fungal cells, and affecting the integrity of cell walls

Inactive Publication Date: 2005-01-06
DEV PARTNERS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a group of structurally-related compounds disclosed below that are effective as inhibitors of protein prenylation.

Problems solved by technology

Selective inhibition of the fungal enzyme would diminish cell wall integrity, and thus be lethal to fungal cells.
The effectiveness and specificity of these inhibitors vary widely, as do their chemical structures, and many of them are difficult to synthesize and purify.

Method used

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  • Prenylation inhibitors containing dimethylcyclobutane and methods of their synthesis and use
  • Prenylation inhibitors containing dimethylcyclobutane and methods of their synthesis and use
  • Prenylation inhibitors containing dimethylcyclobutane and methods of their synthesis and use

Examples

Experimental program
Comparison scheme
Effect test

example 1

This example illustrates methods for synthesizing compounds of the present invention.

Coupling to Polystyrene Rink resin

About 42 grams (g) of Fmoc-protected Rink polystyrene resin and about 100 milliliter (ml) of dimethylformamide (DMF) were combined in a 500 ml peptide vessel and shaken for about 5 minutes. The DMF was removed, about 200 ml of 20% piperidine in DMF was added to the vessel, and the mixture was shaken for 30 minutes. This step was repeated prior to the solvent being removed. Following removal of the solvent, the resin was deprotected by being washed 3 times with 30 ml of DMF and twice with 200 ml of 1-methyl-2-pyrrolidinone (NMP). The resin was then dried for about 1 hour in vacuo. About 2 equivalents of an amino acid, about 2 equivalents of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), about 2 equivalents of N-hydroxybenzotriazole (HOBt), and about 200 ml of NMP were mixed in a 250 ml beaker. Before addition to the peptide vesse...

example 2

This example shows the formation of the pyrazole ring having different substituents. Referring to FIG. 4, the individual intermediates were formed under the following reaction conditions.

2-Hydroxy4-oxo4-pyridin-3-ylbut-2-enoic acid methyl ester (1). Acetyl pyridine (1.81 mL, 16.5 mmol) and methyl oxalate (3.12 g, 26.4 mmol) were dissolved in MeOH (30 mL, anhydrous). Sodium methoxide (6.9 mL, 25% in MeOH) was added over 10 min. Reaction solidified and was complete after 15 minutes. The solid mass was dissolved when acidified with HCl (10%, aqueous). The pH was then adjusted with NH4OH (conc) until precipitation ceased. The resulting solid was taken up in EtOAc. The aqueous layer was removed and extracted twice with EtOAc. The combined EtOAc layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. Collected 1 (2.90 g, 85%) as an off-white solid.

1-(3,4-Dichlorophenyl)-5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid methyl ester hydrochloride (2)...

example 3

This example demonstrates the synthesis of prenylation inhibitors of the present invention with different substituent on the pyrazole ring. Referring to FIG. 5, the individual intermediates were formed under the following reaction conditions.

(12). NaOEt (21% w / v EtOH; 2.04 g, 30 mmol) was added to a dry flask under N2. The mixture was cooled to 0C. During the cooling process, ethyl nicotinate (4.53 g, 30 mmol) was added in one portion. y-Butyrolactone (2.58 g, 30 mmol) was added dropwise over 30 min. The mixture was stirred at 0° C. for 1 h. Upon removal of the ice bath the reaction was allowed to warm to rt and was heated to ˜65° C. overnight. The solvent was removed in vacuo and the residue was diluted with H2O, and extracted with diethyl ether to remove any unreacted starting material. The aqueous phase was acidified with 1N HCl and extracted with DCM. The organic layer was washed with H2O, brine, and dried (Na2SO4), to yield 12 (2.87 g, 50%) as a brown oil.

(13). To a soluti...

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Abstract

The present invention is directed to compounds useful in the treatment of diseases associated with prenylation of proteins and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising same, and to methods for inhibiting protein prenylation in an organism using the same.

Description

FIELD OF THE INVENTION This present invention relates to a class of novel compounds useful in the treatment of diseases associated with the prenylation of proteins. BACKGROUND OF THE INVENTION The mammalian Ras proteins are a family of guanosine triphosphate (GTP) binding and hydrolyzing proteins that regulate cell growth and differentiation. Their overproduction or mutation can lead to uncontrolled cell growth, and has been implicated as a cause or aggravating factor in a variety of diseases including cancer, restenosis, psoriasis, endometriosis, atherosclerosis, viral or yeast infection, and corneal neovascularization. Ras proteins share characteristic C-terminal sequences termed the CAAX motif, wherein C is Cys, A is an amino acid, usually an aliphatic amino acid, and X is an aliphatic amino acid or other type of amino acid. The biological activity of the proteins is dependent upon the post-translational modification of these sequences by isoprenoid lipids. For proteins having...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D231/12C07D231/22C07D401/04C07D401/14C07D403/04C07D409/14C07D417/04C07D471/04
CPCC07D231/12C07D231/22C07D401/04C07D401/14C07D471/04C07D409/14C07D413/04C07D417/04C07D403/04A61P35/00
Inventor BROWN, BRADLEY B.REHDER, KENNETH S.STRACHAN, JON-PAULEAVES, JERON H.LOWDEN, CHRISTOPHER T.
Owner DEV PARTNERS
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